In all living organisms, heat shock and other stresses cause induction of a group of heat shock proteins (Hsps), which play an important role in protection of cells against adverse effects of stresses. The age-related attenuation of inducibility of Hsps correlates with the increase in morbidity and mortality of aged organisms exposed to hyperthermia. For example, the rate of heat stroke is more than 10-fold higher for persons of 65 years or older as compared to younger individuals. This suggests that basic physiological changes in the organism, rather than underlying diseases, may be responsible for the age-related increase in heat stroke. Diminishing inducibility of Hsps and increasing sensitivity to heat shock with aging has also been observed in cell cultures. Indeed, cells isolated from the aged organisms, as well as cells isolated from young organisms and aged in culture, show reduced ability to induce Hsps upon stress and increased stress-sensitivity. Therefore, elucidating molecular events underlying age-related sensitivity to stress at the cellular level would help to understand responses to stresses by aged organisms.
Over the past years, a number of studies have shown that the major heat-inducible protein, Hsp72, is critical for protection of cells and tissues from heat shock and other stresses. Hsp72 functions as molecular chaperone in refolding and degradation of damaged proteins. This has led to the common assumption that chaperoning activities of Hsp72 determine its role in ability of a cell to protect itself against stresses. Upon exposure to stresses that lead to a massive protein damage and necrotic death, the anti-aggregating and protein refolding activities of Hsp72 may indeed become critical for cell protection. On the other hand, upon exposure to stresses that lead to apoptosis, the protective function of Hsp72 could be fully accounted for by its distinct role in cell signaling. Under these conditions, protein damage on its own is not sufficient for cell death because suppression of the apoptotic signaling pathway restores cell viability. Indeed, specific inactivation of a stress-kinase JNK, an essential element of this signaling pathway, prevents stress-induced apoptosis. This was demonstrated by interruption of JNK signaling pathway either immediately upstream of JNK (by expression of dominant-negative mutants of JNK activator SEK1) or immediately downstream of JNK (by expression of a dominant negative mutant of c-jun). Recently it was demonstrated that the distinct role of Hsp72 in protection of cells from heat-induced apoptosis is, in fact, suppression of JNK activation. A greater understanding of the role of Hsp72 in aged cells could have important therapeutic applications.